Transgenerational telomere erosion in the monogametic sex: human telomeres progressively erode in the female germline and do not lengthen in aged testes.

Abstract

Long telomeres, the protective caps of eukaryotic chromosomes, which erode during aging, have been the symbol of youth and regenerative potential. It therefore came as a surprise, when several cross-sectional studies reported that telomeres in sperm cells of old men are longer than in young men and that paternal age is positively linked to telomere length of children. To explain the puzzling data, several theories have been put forward, from Darwinian selection to high telomerase activity or alternative telomere lengthening in sperms of geriatrics. Unfortunately, the idea of a birth-cohort effect has been ignored, despite existing theoretical models and despite findings of progressive telomere erosion between human generations. The old theoretical model of progressive telomere erosion in the female germline is discussed here and updated with the hypothesis that progressive telomere erosion is tied to the monogametic sex in all higher animals. Longitudinal studies of germline telomere length in humans are much needed, since a limited regenerative capacity of somatic tissues will most likely result in an increase in and earlier onset of the so-called age-associated diseases.

Concept of transgenerational telomere erosion in the female germline (as published in [, ]): High expression levels of telomerase stabilize sperm telomeres in human males throughout reproductive life (flat red line). Already at prenatal age, the ovaries are populated with millions of primary oocytes during oocytogenesis. Only a small fraction of them complete meiosis and start ovulating in a serial manner at menarche. It has been postulated that long-telomered ova are utilized first [], whereas female germ cells with critically short telomeres are last (descending blue line). Support for this hypothesis comes from the well-known fact that middle-aged women have an increased risk of aneuploid pregnancies (e.g. Down’s syndrome), which rapidly increases during the second half of the female reproductive period []. In diploid organisms, at conception, one chromosome comes from the mother the other from the father, resulting in a combination of parental chromosomes and thereby telomere lengths in the fertilized egg (junctions of red & blue lines). Older males bypass the telomere loss of 1–2 generations and on average have longer sperm telomeres than their younger contemporaries. Several scenarios and combinations are highlighted in the graph (colored broken lines). The negative maternal age effect on offspring’s telomeres is masked by the fact that older women tend to have male partners of similar advanced age (blue broken line). The positive paternal age effect is pronounced, because the reproductive period of males is twice as long as in females and therefore old fathers can bypass the telomere loss of two generations (yellow and green broken lines)